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Pagnon de la Vega, M., Syvänen, S., Giedraitis, V., Hooley, M., Konstantinidis, E., Meier, S. R., . . . Sehlin, D. (2024). Altered amyloid-β structure markedly reduces gliosis in the brain of mice harboring the Uppsala APP deletion. Acta neuropathologica communications, 12(1), Article ID 22.
Open this publication in new window or tab >>Altered amyloid-β structure markedly reduces gliosis in the brain of mice harboring the Uppsala APP deletion
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2024 (English)In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 12, no 1, article id 22Article in journal (Refereed) Published
Abstract [en]

Deposition of amyloid beta (Aβ) into plaques is a major hallmark of Alzheimer’s disease (AD). Different amyloid precursor protein (APP) mutations cause early-onset AD by altering the production or aggregation properties of Aβ. We recently identified the Uppsala APP mutation (APPUpp), which causes Aβ pathology by a triple mechanism: increased β-secretase and altered α-secretase APP cleavage, leading to increased formation of a unique Aβ conformer that rapidly aggregates and deposits in the brain. The aim of this study was to further explore the effects of APPUpp in a transgenic mouse model (tg-UppSwe), expressing human APP with the APPUpp mutation together with the APPSwe mutation. Aβ pathology was studied in tg-UppSwe brains at different ages, using ELISA and immunohistochemistry. In vivo PET imaging with three different PET radioligands was conducted in aged tg-UppSwe mice and two other mouse models; tg-ArcSwe and tg-Swe. Finally, glial responses to Aβ pathology were studied in cell culture models and mouse brain tissue, using ELISA and immunohistochemistry. Tg-UppSwe mice displayed increased β-secretase cleavage and suppressed α-secretase cleavage, resulting in AβUpp42 dominated diffuse plaque pathology appearing from the age of 5–6 months. The γ-secretase cleavage was not affected. Contrary to tg-ArcSwe and tg-Swe mice, tg-UppSwe mice were [11C]PiB-PET negative. Antibody-based PET with the 3D6 ligand visualized Aβ pathology in all models, whereas the Aβ protofibril selective mAb158 ligand did not give any signals in tg-UppSwe mice. Moreover, unlike the other two models, tg-UppSwe mice displayed a very faint glial response to the Aβ pathology. The tg-UppSwe mouse model thus recapitulates several pathological features of the Uppsala APP mutation carriers. The presumed unique structural features of AβUpp42 aggregates were found to affect their interaction with anti-Aβ antibodies and profoundly modify the Aβ-mediated glial response, which may be important aspects to consider for further development of AD therapies.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2024
Keywords
Alzheimer's disease (AD), Amyloid precursor protein (APP), Amyloid-beta (A beta), PET imaging, Microglia, Astrocytes, Immunotherapy
National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:uu:diva-523728 (URN)10.1186/s40478-024-01734-x (DOI)001158145500001 ()38317196 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationUppsala UniversitySwedish Research Council, 2016‑02120Swedish Research Council, 2021‑01083Swedish Research Council, 2021‑03524AlzheimerfondenThe Swedish Brain FoundationTorsten Söderbergs stiftelseÅhlén-stiftelsenMagnus Bergvall FoundationStiftelsen Gamla TjänarinnorGun och Bertil Stohnes StiftelseKonung Gustaf V:s och Drottning Victorias FrimurarestiftelseStiftelsen Sigurd och Elsa Goljes minne
Note

De två sista författarna delar sistaförfattarskapet

Available from: 2024-02-26 Created: 2024-02-26 Last updated: 2024-02-26Bibliographically approved
Eltom, K., Mothes, T., Libard, S., Ingelsson, M. & Erlandsson, A. (2024). Astrocytic accumulation of tau fibrils isolated from Alzheimer’s disease brains induces inflammation, cell-to-cell propagation and neuronal impairment. Acta neuropathologica communications, 12(1), Article ID 34.
Open this publication in new window or tab >>Astrocytic accumulation of tau fibrils isolated from Alzheimer’s disease brains induces inflammation, cell-to-cell propagation and neuronal impairment
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2024 (English)In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 12, no 1, article id 34Article in journal (Refereed) Published
Abstract [en]

Accumulating evidence highlights the involvement of astrocytes in Alzheimer’s disease (AD) progression. We have previously demonstrated that human iPSC-derived astrocytes ingest and modify synthetic tau fibrils in a way that enhances their seeding efficiency. However, synthetic tau fibrils differ significantly from in vivo formed fibrils. To mimic the situation in the brain, we here analyzed astrocytes’ processing of human brain-derived tau fibrils and its consequences for cellular physiology. Tau fibrils were extracted from both AD and control brains, aiming to examine any potential differences in astrocyte response depending on the origin of fibrils. Our results show that human astrocytes internalize, but fail to degrade, both AD and control tau fibrils. Instead, pathogenic, seeding capable tau proteoforms are spread to surrounding cells via tunneling nanotubes and exocytosis. Notably, accumulation of AD tau fibrils induces a stronger reactive state in astrocytes, compared to control fibrils, evident by the augmented expression of vimentin and GFAP, as well as by an increased secretion of the pro-inflammatory cytokines IL-8 and MCP-1. Moreover, conditioned media from astrocytes with AD tau fibril deposits induce synapse and metabolic impairment in human iPSC-derived neurons. Taken together, our data suggest that the accumulation of brain-derived AD tau fibrils induces a more robust inflammatory and neurotoxic phenotype in human astrocytes, accentuating the nature of tau fibrils as an important contributing factor to inflammation and neurodegeneration in AD. 

Place, publisher, year, edition, pages
BioMed Central (BMC), 2024
Keywords
Alzheimer’s disease; tau; astrocytes; brain-derived fibrils; inflammation; neurons
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-523823 (URN)10.1186/s40478-024-01745-8 (DOI)001176894300001 ()38409026 (PubMedID)
Funder
Åhlén-stiftelsen, 233044The Swedish Brain Foundation, FO2022-0083Stiftelsen Gamla Tjänarinnor, 2021 − 01171O.E. och Edla Johanssons vetenskapliga stiftelseBertil and Ebon Norlin Foundation for Medical ResearchGun och Bertil Stohnes StiftelseSwedish Fund for Research Without Animal Experiments, F2022-0004Uppsala University
Available from: 2024-02-23 Created: 2024-02-23 Last updated: 2024-04-10Bibliographically approved
Rystedt, E., Moren, J., Lindbäck, J., Tedim Cruz, V., Ingelsson, M., Kilander, L., . . . Westman, G. (2024). Validation of a web-based self-administered test for cognitive assessment in a Swedish geriatric setting. PLOS ONE, 19(2), Article ID e0297575.
Open this publication in new window or tab >>Validation of a web-based self-administered test for cognitive assessment in a Swedish geriatric setting
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2024 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 19, no 2, article id e0297575Article in journal (Refereed) Published
Abstract [en]

Computerized cognitive tests have the potential to cost-effectively detect and monitor cognitive impairments and thereby facilitate treatment for these conditions. However, relatively few of these tests have been validated in a variety of populations. Brain on Track, a self-administered web-based test, has previously been shown to have a good ability to differentiate between healthy individuals and patients with cognitive impairment in Portuguese populations. The objective of this study was to validate the differential ability and evaluate the usability of Brain on Track in a Swedish memory clinic setting. Brain on Track was administered to 30 patients with mild cognitive impairment/mild dementia and 30 healthy controls, all scheduled to perform the test from home after one week and after three months. To evaluate the usability, the patient group was interviewed after completion of the testing phase. Patients scored lower than healthy controls at both the first (median score 42.4 vs 54.1, p<0.001) and the second test (median score 42.3 vs 55.0, p<0.001). The test-retest intra-class correlation was 0.87. A multiple logistic regression model accounting for effects of age, gender and education rendered an ability of Brain on Track to differentiate between the groups with an area under the receiver operation characteristics curve of 0.90 for the first and 0.88 for the second test. In the subjective evaluation, nine patients left positive comments, nine were negative whereas five left mixed comments regarding the test experience. Sixty percent of patients had received help from relatives to log on to the platform. In conclusion, Brain on Track performed well in differentiating healthy controls from patients with cognitive impairment and showed a high test-retest reliability, on par with results from previous studies. However, the substantial proportion of patients needing help to log in could to some extent limit an independent use of the platform.

Place, publisher, year, edition, pages
Public Library of Science (PLoS), 2024
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-526197 (URN)10.1371/journal.pone.0297575 (DOI)001158449800007 ()38300935 (PubMedID)
Available from: 2024-04-11 Created: 2024-04-11 Last updated: 2024-04-11Bibliographically approved
Brolin, E., Ingelsson, M., Bergström, J. & Erlandsson, A. (2023). Altered Distribution of SNARE Proteins in Primary Neurons Exposed to Different Alpha-Synuclein Proteoforms. Cellular and molecular neurobiology, 43(6), 3023-3035
Open this publication in new window or tab >>Altered Distribution of SNARE Proteins in Primary Neurons Exposed to Different Alpha-Synuclein Proteoforms
2023 (English)In: Cellular and molecular neurobiology, ISSN 0272-4340, E-ISSN 1573-6830, Vol. 43, no 6, p. 3023-3035Article in journal (Refereed) Published
Abstract [en]

Growing evidence indicates that the pathological alpha-synuclein (a-syn) aggregation in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) starts at the synapses. Physiologic a-syn is involved in regulating neurotransmitter release by binding to the SNARE complex protein VAMP-2 on synaptic vesicles. However, in which way the SNARE complex formation is affected by a-syn pathology remains unclear. In this study, primary cortical neurons were exposed to either a-syn monomers or preformed fibrils (PFFs) for different time points and the effect on SNARE protein distribution was analyzed with a novel proximity ligation assay (PLA). Short-term exposure to monomers or PFFs for 24 h increased the co-localization of VAMP-2 and syntaxin-1, but reduced the co-localization of SNAP-25 and syntaxin-1, indicating a direct effect of the added a-syn on SNARE protein distribution. Long-term exposure to a-syn PFFs for 7 d reduced VAMP-2 and SNAP-25 co-localization, although there was only a modest induction of ser129 phosphorylated (pS129) a-syn. Similarly, exposure to extracellular vesicles collected from astrocytes treated with a-syn PFFs for 7 d influenced VAMP-2 and SNAP-25 co-localization despite only low levels of pS129 a-syn being formed. Taken together, our results demonstrate that different a-syn proteoforms have the potential to alter the distribution of SNARE proteins at the synapse.

Place, publisher, year, edition, pages
Springer, 2023
Keywords
Alpha-synuclein, SNARE, Proximity ligation assay, Synapse, Primary neurons
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-511391 (URN)10.1007/s10571-023-01355-3 (DOI)000981547700001 ()37130995 (PubMedID)
Funder
Swedish Research Council, 202102563Parkinsonfonden, 1405/2022The Swedish Brain Foundation, FO2022-0062
Available from: 2023-09-22 Created: 2023-09-22 Last updated: 2023-09-22Bibliographically approved
Mothes, T., Portal, B., Konstantinidis, E., Eltom, K., Libard, S., Streubel-Gallasch, L., . . . Erlandsson, A. (2023). Astrocytic uptake of neuronal corpses promotes cell-to-cell spreading of tau pathology. Acta neuropathologica communications, 11(1), Article ID 97.
Open this publication in new window or tab >>Astrocytic uptake of neuronal corpses promotes cell-to-cell spreading of tau pathology
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2023 (English)In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 11, no 1, article id 97Article in journal (Refereed) Published
Abstract [en]

Tau deposits in astrocytes are frequently found in Alzheimer's disease (AD) and other tauopathies. Since astrocytes do not express tau, the inclusions have been suggested to be of neuronal origin. However, the mechanisms behind their appearance and their relevance for disease progression remain unknown. Here we demonstrate, using a battery of experimental techniques that human astrocytes serve as an intermediator, promoting cell-to-cell spreading of pathological tau. Human astrocytes engulf and process, but fail to fully degrade dead neurons with tau pathology, as well as synthetic tau fibrils and tau aggregates isolated from AD brain tissue. Instead, the pathogenic tau is spread to nearby cells via secretion and tunneling nanotube mediated transfer. By performing co-culture experiments we could show that tau-containing astrocytes induce tau pathology in healthy human neurons directly. Furthermore, our results from a FRET based seeding assay, demonstrated that the tau proteoforms secreted by astrocytes have an exceptional seeding capacity, compared to the original tau species engulfed by the cells. Taken together, our study establishes a central role for astrocytes in mediating tau pathology, which could be of relevance for identifying novel treatment targets for AD and other tauopathies.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2023
Keywords
Alzheimer's disease, Tau, Astrocytes, Neurons, Cell-to-cell spreading, hiPSCs
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-506917 (URN)10.1186/s40478-023-01589-8 (DOI)001007228100001 ()37330529 (PubMedID)
Funder
Uppsala UniversitySwedish Research Council, 2021–02563Alzheimerfonden, AF‑968209Åhlén-stiftelsen, 213021The Swedish Brain Foundation, FO2021‑0174Stiftelsen Gamla Tjänarinnor, 2021–01171O.E. och Edla Johanssons vetenskapliga stiftelseOlle Engkvists stiftelse, 215–0399Bertil and Ebon Norlin Foundation for Medical ResearchGun och Bertil Stohnes Stiftelse
Available from: 2023-06-30 Created: 2023-06-30 Last updated: 2024-02-23Bibliographically approved
Zielinski, M., Peralta Reyes, F. S., Gremer, L., Schemmert, S., Frieg, B., Schäfer, L. U., . . . Schröder, G. F. (2023). Cryo-EM of Aβ fibrils from mouse models find tg-APPArcSwe fibrils resemble those found in patients with sporadic Alzheimer's disease. Nature Neuroscience, 26(12), 2073-2080
Open this publication in new window or tab >>Cryo-EM of Aβ fibrils from mouse models find tg-APPArcSwe fibrils resemble those found in patients with sporadic Alzheimer's disease
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2023 (English)In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 26, no 12, p. 2073-2080Article in journal (Refereed) Published
Abstract [en]

The use of transgenic mice displaying amyloid-β (Aβ) brain pathology has been essential for the preclinical assessment of new treatment strategies for Alzheimer's disease. However, the properties of Aβ in such mice have not been systematically compared to Aβ in the brains of patients with Alzheimer's disease. Here, we determined the structures of nine ex vivo Aβ fibrils from six different mouse models by cryogenic-electron microscopy. We found novel Aβ fibril structures in the APP/PS1, ARTE10 and tg-SwDI models, whereas the human type II filament fold was found in the ARTE10, tg-APPSwe and APP23 models. The tg-APPArcSwe mice showed an Aβ fibril whose structure resembles the human type I filament found in patients with sporadic Alzheimer's disease. A detailed assessment of the Aβ fibril structure is key to the selection of adequate mouse models for the preclinical development of novel plaque-targeting therapeutics and positron emission tomography imaging tracers in Alzheimer's disease.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-526548 (URN)10.1038/s41593-023-01484-4 (DOI)001106141500001 ()37973869 (PubMedID)
Available from: 2024-04-12 Created: 2024-04-12 Last updated: 2024-06-13Bibliographically approved
van de Vegte, Y., Eppinga, R. P., van der Ende, M. Y., Hagemeijer, Y., Mahendran, Y. V., Salfati, E. Y., . . . van der Harst, P. (2023). Genetic insights into resting heart rate and its role in cardiovascular disease. Nature Communications, 14(1), Article ID 4646.
Open this publication in new window or tab >>Genetic insights into resting heart rate and its role in cardiovascular disease
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2023 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 14, no 1, article id 4646Article in journal (Refereed) Published
Abstract [en]

The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Cardiac and Cardiovascular Systems Medical Genetics
Identifiers
urn:nbn:se:uu:diva-511622 (URN)10.1038/s41467-023-39521-2 (DOI)001042222000014 ()37532724 (PubMedID)
Funder
Wellcome trust, 202802/Z/16/Z
Available from: 2023-09-15 Created: 2023-09-15 Last updated: 2023-10-03Bibliographically approved
Braun, M., Boström, G., Ingelsson, M., Kilander, L., Löwenmark, M., Nyholm, D., . . . Virhammar, J. (2023). Levels of inflammatory cytokines MCP-1, CCL4, and PD-L1 in CSF differentiate idiopathic normal pressure hydrocephalus from neurodegenerative diseases. Fluids and Barriers of the CNS, 20, Article ID 72.
Open this publication in new window or tab >>Levels of inflammatory cytokines MCP-1, CCL4, and PD-L1 in CSF differentiate idiopathic normal pressure hydrocephalus from neurodegenerative diseases
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2023 (English)In: Fluids and Barriers of the CNS, E-ISSN 2045-8118, Vol. 20, article id 72Article in journal (Refereed) Published
Abstract [en]

Background: Neuroinflammatory processes have been suggested to play a role in the pathophysiology of neurodegenerative diseases and post-hemorrhagic hydrocephalus, but have rarely been investigated in patients with idiopathic normal pressure hydrocephalus (iNPH). The aim of this study was to investigate whether levels of inflammatory proteins in CSF are different in iNPH compared to healthy controls and patients with selected neurodegenerative disorders, and whether any of these markers can aid in the differential diagnosis of iNPH.

Methods: Lumbar CSF was collected from 172 patients from a single center and represented iNPH (n = 74), Alzheimer's disease (AD) (n = 21), mild cognitive impairment (MCI) due to AD (n = 21), stable MCI (n = 22), frontotemporal dementia (n = 13), and healthy controls (HC) (n = 21). Levels of 92 inflammatory proteins were analyzed using a proximity extension assay. As a first step, differences between iNPH and HC were investigated, and proteins that differed between iNPH and HC were then compared with those from the other groups. The linear regressions were adjusted for age, sex, and plate number.

Results: Three proteins showed higher (MCP-1, p = 0.0013; CCL4, p = 0.0008; CCL11, p = 0.0022) and one lower (PD-L1, p = 0.0051) levels in patients with iNPH compared to HC. MCP-1 was then found to be higher in iNPH than in all other groups. CCL4 was higher in iNPH than in all other groups, except in MCI due to AD. PD-L1 was lower in iNPH compared to all other groups, except in stable MCI. Levels of CCL11 did not differ between iNPH and the differential diagnoses. In a model based on the four proteins mentioned above, the mean area under the receiver operating characteristic curve used to discriminate between iNPH and the other disorders was 0.91.

Conclusions: The inflammatory cytokines MCP-1 and CCL4 are present at higher-and PD-L1 at lower-levels in iNPH than in the other investigated diagnoses. These three selected cytokines may have diagnostic potential in the work-up of patients with iNPH.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2023
Keywords
Normal pressure hydrocephalus, MCP-1, CCL4, PD-L1, Biomarkers, Cerebrospinal fluid, Neuroinflammation, Proteomics
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:uu:diva-516881 (URN)10.1186/s12987-023-00472-x (DOI)001097538500001 ()37833765 (PubMedID)
Funder
Swedish Research Council, 2021-02189Swedish Society for Medical Research (SSMF), SG-22-0192Region UppsalaUppsala University
Available from: 2023-12-07 Created: 2023-12-07 Last updated: 2024-01-17Bibliographically approved
Le Guen, Y., Luo, G., Ambati, A., Damotte, V., Jansen, I., Yu, E., . . . Mignot, E. (2023). Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes. Proceedings of the National Academy of Sciences of the United States of America, 120(36), Article ID e2302720120.
Open this publication in new window or tab >>Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes
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2023 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 120, no 36, article id e2302720120Article in journal (Refereed) Published
Abstract [en]

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1* 04:07, and intermediary with HLA-DRB1* 04:01 and HLA- DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased A beta 42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

Place, publisher, year, edition, pages
Proceedings of the National Academy of Sciences (PNAS), 2023
Keywords
HLA, Alzheimer's dementia, Parkinson's disease, neurodegeneration, autoimmunity
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:uu:diva-519562 (URN)10.1073/pnas.2302720120 (DOI)001119291700001 ()37643212 (PubMedID)
Available from: 2024-01-08 Created: 2024-01-08 Last updated: 2024-01-08Bibliographically approved
Donadio, V., Incensi, A., Rizzo, G., Westermark, G. T., Devigili, G., De Micco, R., . . . Liguori, R. (2023). Phosphorylated α-synuclein in skin Schwann cells: a new biomarker for multiple system atrophy. Brain, 146(3), 1065-1074
Open this publication in new window or tab >>Phosphorylated α-synuclein in skin Schwann cells: a new biomarker for multiple system atrophy
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2023 (English)In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 146, no 3, p. 1065-1074Article in journal (Refereed) Published
Abstract [en]

Multiple system atrophy (MSA) is characterized by accumulation of phosphorylated α-synuclein (p-syn) as glial cytoplasmic inclusions in the brain and a specific biomarker for this disorder is urgently needed. We aimed at investigating if p-syn can also be detected in skin Remak non-myelinating Schwann cells (RSCs) as Schwann cell cytoplasmic inclusions (SCCi) and may represent a reliable clinical biomarker for MSA.

This cross-sectional diagnostic study evaluated skin p-syn in 96 patients: 46 with probable MSA (29 with parkinsonism type MSA and 17 with cerebellar type MSA), 34 with Parkinson's disease (PD) and 16 with dementia with Lewy bodies (DLB). We also included 50 healthy control subjects. Patients were recruited from five different medical centres. P-syn aggregates in skin sections were stained by immunofluorescence, followed by analyses with confocal microscopy and immuno-electron microscopy. All analyses were performed in a blinded fashion.

Overall, p-syn aggregates were found in 78% of MSA patients and 100% of patients with PD/DLB, whereas they could not be detected in controls. As for neuronal aggregates 78% of MSA patients were positive for p-syn in somatic neurons, whereas all PD/DLB patients were positive in autonomic neurons. When analysing the presence of p-syn in RSCs, 74% of MSA patients were positive, whereas no such SCCi could be observed in PD/DLB patients. Analyses by immuno-electron microscopy confirmed that SCCi were only found in cases with MSA and thus absent in those with PD/DLB.

In conclusion, our findings demonstrate that (i) fibrillar p-syn in RSCs is a pathological hallmark of MSA and may be used as a specific and sensitive disease biomarker; (ii) in Lewy body synucleinopathies (PD/DLB) only neurons contain p-syn deposits; and (iii) the cell-specific deposition of p-syn in the skin thus mirrors that of the brain in many aspects and suggests that non-myelinated glial cells are also involved in the MSA pathogenesis.

Place, publisher, year, edition, pages
Oxford University Press, 2023
Keywords
multiple system atrophy, skin non-myelinating Schwann cell, fibrillar alpha-synuclein, skin biopsy, biomarker
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:uu:diva-501866 (URN)10.1093/brain/awac124 (DOI)000926054300001 ()35552610 (PubMedID)
Note

Title in Web of Science: Phosphorylated alpha-synuclein in skin Schwann cells: a new biomarker for multiple system atrophy

Available from: 2023-05-16 Created: 2023-05-16 Last updated: 2023-05-16Bibliographically approved
Projects
Alpha-synuclein pathogenesis - novel targets for therapy and diagnostics in Parkinson´s disease [2011-04519_VR]; Uppsala UniversityA European DNA bank for deciphering the missing heritability of Alzheimer’s disease [2015-06799_VR]; Uppsala UniversityDevelopment of gene therapy targeting amyloid-Œ≤ and Œ±-synuclein on cell and mouse models for Alzheimer’s disease and Parkinson’s disease [2018-03075_VR]; Uppsala University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-5466-8370

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